Associated disorders

The CACNA1C gene is associated with autosomal dominant Timothy syndrome, also known as long QT syndrome (LQTS) type 8 (MedGen UID: 331395), Brugada syndrome (BrS) (MedGen UID: 395633), and short QT syndrome (SQTS) (MedGen UID: 378835).

Pathogenic CACNA1C variants cause 100% of cases of Timothy syndrome, a subtype of LQTS, although they are a rare cause of LQTS overall. CACNA1C is also associated with an unknown percentage of clinical cases of SQTS and BrS.

The CACNA1C gene encodes the alpha-1 C subunit of a voltage-dependent calcium channel. Calcium channels control the flow of calcium ions in cardiac muscle. The electrical activity of cardiac muscle is controlled by the movement of potassium, sodium, and calcium ions across cardiac muscle cell membranes. Pathogenic variants in genes that encode subunits of cardiac calcium channels are known to cause inherited cardiac arrhythmias.

  1. NCBI GeneReviews. Long QT Syndrome. PMID: 20301308
  2. Hedley, PL, et al. The genetic basis of long QT and short QT syndromes: a mutation update. Hum. Mutat. 2009; 30(11):1486-511. PMID: 19862833
  3. Gillis, J, et al. Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: expanding the spectrum of Timothy syndrome. Am. J. Med. Genet. A. 2012; 158A(1):182-7. doi: 10.1002/ajmg.a.34355. PMID: 22106044
  4. Splawski, I, et al. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc. Natl. Acad. Sci. U.S.A. 2005; 102(23):8089-96; discussion 8086-8. doi: 10.1073/pnas.0502506102. PMID: 15863612
  5. Burashnikov, E, et al. Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm. 2010; 7(12):1872-82. doi: 10.1016/j.hrthm.2010.08.026. PMID: 20817017
  6. Brugada, R, et al. Brugada Syndrome. 2005 Mar 31. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: PMID: 20301690
  7. Antzelevitch, C, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007; 115(4):442-9. doi: 10.1161/CIRCULATIONAHA.106.668392. PMID: 17224476
  8. Napolitano, C. et al. Timothy Syndrome. 2006 Feb 15. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: PMID: 20301577

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
CACNA1C NM_000719.6